22q11.2 deletion syndrome, which has several presentations including DiGeorge syndrome (DGS), DiGeorge anomaly,[2][3]velocardiofacial syndrome, Shprintzen syndrome, conotruncal anomaly face syndrome, Strong syndrome, congenital thymic aplasia, and thymic hypoplasia, is a syndrome caused by the deletion of a small piece of chromosome 22. The deletion occurs near the middle of the chromosome at a location designated 22q11.2—signifying its location on the long arm of one of the pair of chromosomes 22, on region 1, band 1, sub-band 2. The inheritance pattern is autosomal dominant and it has a prevalence estimated at 1:4000.[4] The syndrome was described in 1968 by the pediatric endocrinologistAngelo DiGeorge.[5][6] 22q11 deletion is also associated with truncus arteriosus and tetralogy of Fallot.[7]

The features of this syndrome vary widely, even among members of the same family, and affect many parts of the body. Characteristic signs and symptoms may include birth defects such as congenital heart disease, defects in the palate, most commonly related to neuromuscular problems with closure (velopharyngeal insufficiency), learning disabilities, mild differences in facial features, and recurrent infections. Infections are common in children due to problems with the immune system's T-cell-mediated response that in some patients is due to an absent or hypoplasticthymus. 22q11.2 deletion syndrome may be first spotted when an affected newborn has heart defects or convulsions from hypocalcemia due to malfunctioning parathyroid glands and low levels of parathyroid hormone (parathormone). Affected individuals may also have any other kind of birth defect including kidney abnormalities and significant feeding difficulties as babies. Disorders such as hypothyroidism and hypoparathyroidism or thrombocytopenia (low platelet levels), and psychiatric illnesses are common late-occurring features.[8] Microdeletions in chromosomal region 22q11.2 are associated with a 20 to 30-fold increased risk of schizophrenia.[9]

Studies provide various rates of 22q11.2 deletion syndrome in schizophrenia, ranging from 0.5 to 2.0% and averaging about 1.0%, compared with the overall estimated 0.025% risk of the 22q11.2 deletion syndrome in the general population.[10]

Salient features can be summarized using the mnemonic CATCH-22 to describe DiGeorge syndrome, with the 22 to remind one the chromosomal abnormality is found on the 22 chromosome, as below:[11]

The signs and symptoms of 22q11 deletion syndrome are so varied that different groupings of its features were once regarded as separate conditions. These original classifications included velocardiofacial syndrome, Shprintzen syndrome, DiGeorge sequence/syndrome, Sedlackova syndrome, and conotruncal anomaly face syndrome. All are now understood to be presentations of a single syndrome.

The syndrome is caused by genetic deletions (loss of a small part of the genetic material) found on the long arm of one of the two 22nd chromosomes. Very rarely, patients with somewhat similar clinical features may have deletions on the short arm of chromosome 10.

The mechanism that causes all of the associated features of the syndrome is unknown. 22q11.2 deletion syndrome may involve migration defects of neural crest-derived tissues, particularly affecting development of the third and fourth branchial pouches (pharyngeal pouches). This affects the thymus gland, a mediastinal organ largely responsible for differentiation and induction of tolerance in T-cells, and the parathyroid glands, responsible for regulation of blood calcium levels.[12]

No cure is known for 22q11.2 deletion syndrome. Certain individual features are treatable using standard treatments. The key is to identify each of the associated features and manage each using the best available treatments.

For example, in children, it is important that the immune problems are identified early, as special precautions are required regarding blood transfusion and immunization with live vaccines. Thymustransplantation can be used to address absence of the thymus in the rare, so-called "complete" DiGeorge syndrome.[13] Bacterial infections are treated with antibiotics. Cardiac surgery is often required for congenital heart abnormalities. Hypoparathyroidism causing hypocalcaemia often requires lifelong vitamin D and calcium supplements.

The 22q11.2 deletion syndrome is diagnosed in individuals with a submicroscopic deletion of chromosome 22 detected by fluorescence in situ hybridization (FISH), BACs-on-Beads technology, Multiplex ligation-dependent probe amplification (MLPA) or array-comparative genomic hybridization (array-CGH). FISH is done on a blood sample: one DNA probe from the 22q11.2 chromosomal region is used at a time, while with BACs-on-Beads technology, multiple probes from the 22q11.2 region can be used simultaneously. In MLPA testing, various probes for selected regions of 22q11.2 are used to identify microdeletions,[14] but any findings should be further confirmed by other techniques (FISH or array-CGH). Array-CGH is a technique of molecular karyotype where a large number of probes are embedded in a chip to screen the entire genome for deletions or duplications. Array-CGH can identify the extent of the microdeletion in 22q11.2 chromosomal region and characterize any missing genes, leading to a better evaluation of signs, symptoms, and prognosis of the syndrome. Such genetic testing is widely available for the clinical and prenatal testing of the 22q11.2 deletion syndrome. Fewer than 5% of individuals with clinical symptoms of the 22q11.2 deletion syndrome have normal routine cytogenetic studies and negative FISH testing. Some cases of DiGeorge syndrome have defects in other chromosomes, notably a deletion in chromosome region 10p14. They may have variant deletions of DiGeorge syndrome that may be detectable on a research basis only or with other more advanced clinical testing method.

Most people with 22q11.2 deletion syndrome are missing about 3 million base pairs on one copy of chromosome 22 in every cell of their body. This region contains about 45 genes, but some of these genes have not been well characterized. A small percentage of affected individuals have shorter deletions in the same region.

Researchers have not yet identified the genes that contribute to the features of 22q11.2 deletion syndrome. They have determined that the loss of one particular gene on chromosome 22, TBX1, is probably responsible for some of the syndrome's characteristic signs (such as heart defects). Carrying only one copy of this gene does not appear to cause learning disabilities, however. Additional genes in the deleted region are likely to contribute to the signs and symptoms of 22q11.2 deletion syndrome and genes outside the 22q11.2 region may also play a role.

The 22q11.2 deletion syndrome can be inherited, but this is the case in the minority of newly diagnosed individuals. Only 5–10% have inherited the 22q11.2 deletion from a parent, whereas about 90–95% of cases have a de novo (new to the family) deletion of 22q11.2. This is because the 22q11.2 region has a structure that makes it highly prone to rearrangements during sperm or egg formation. The deletion is almost equally likely to occur when an egg is formed as when a sperm is formed. The deletion follows standard Mendelian inheritance, so individuals carrying the deletion 22q11.2 have a 50% (one in two) chance of passing it to their offspring. Prenatal testing, such as amniocentesis, is available for pregnancies determined to be at risk. Also, pregnancies with findings of congenital heart disease and/or palate anomalies detected by ultrasound examination may be offered prenatal testing for 22q11.2 deletion syndrome. Because most of the signs of this cluster of defects can also be inherited as autosomal recessive or X-linked traits, only genetic testing of both parents can determine with any certainty the likelihood of these anomalies occurring in any subsequent children.

22q11.2 deletion syndrome affects between one in 2000 and one in 4000 live births.[4] This estimate is based on major birth defects and may be an underestimate, because some individuals with the deletion have few symptoms and may not have been formally diagnosed.

Children with 22q11.2 have a specific profile in neuropsychological tests. They usually have a below- borderline normal IQ, with most individuals having higher scores in the verbal than the nonverbal domains. Some are able to attend normal schools, while others are home-schooled or in special classes.The severity of hypocalcemia early in childhood is associated with autism-like behavioral difficulties.[16]

Adults with DiGeorge syndrome have a specifically high-risk group for developing schizophrenia. About 30% have at least one incident of psychosis and about a quarter develop actual schizophrenia.[17]

Current research demonstrates a unique profile of speech and language impairments is associated with 22q11.2 deletion syndrome. Children often perform lower on speech and language evaluations in comparison to their nonverbal IQ scores.[contradictory] Common problems include hypernasality, language delays, and speech sound errors.[18][19][20]

Hypernasality occurs when air escapes through the nose during the production of oral speech sounds, resulting in reduced intelligibility. This is a common characteristic in the speech and language profile because 69% of children have palatal abnormalities. If the structure of the soft palate velum is such that it does not stop the flow of air from going up to the nasal cavity, it will cause hypernasal speech. This phenomenon is referred as velopharyngeal inadequacy (VPI). Hearing loss can also contribute to increased hypernasality because children with hearing impairments can have difficulty self monitoring their oral speech output. The treatment options available for VPI include prosthesis and surgery.[18][19][21][22][23]

Difficulties acquiring vocabulary and formulating spoken language (expressive language deficits) at the onset of language development are also part of the speech and language profile associated with the 22q11.2 deletion. Vocabulary acquisition is often severely delayed for preschool-age children. In some recent studies, children had a severely limited vocabulary or were still not verbal at 2–3 years of age. School-age children do make progress with expressive language as they mature, but many continue to have delays and demonstrate difficulty when presented with language tasks such as verbally recalling narratives and producing longer and more complex sentences. Receptive language, which is the ability to comprehend, retain, or process spoken language, can also be impaired, although not usually with the same severity as expressive language impairments.[19][22][23][24]

Articulation errors are commonly present in children with 22q11.2 deletion syndrome. These errors include a limited phonemic (speech sound) inventory and the use of compensatory articulation strategies resulting in reduced intelligibility. The phonemic inventory typically produced consists of sounds made in the front or back of the oral cavity such as: /p/, /w/, /m/, /n/, and glottal stops. Sound made in the middle of the mouth are completely absent. Compensatory articulation errors made by this population of children include: glottal stops, nasal substitutions, pharyngeal fricatives, linguapalatal sibilants, reduced pressure on consonant sounds, or a combination of these symptoms. Of these errors, glottal stops have the highest frequency of occurrence. It is reasoned that a limited phonemic inventory and the use of compensatory articulation strategies is present due to the structural abnormalities of the palate. The speech impairments exhibited by this population are more severe during the younger ages and show a trend of gradual improvement as the child matures.[18][22]